Enaminone esters

ABSTRACT

The present invention concerns enaminones having the formula: &lt;IMAGE&gt;  wherein R is from the group consisting of COOCH3 and COOC2H5; R1 is from the group consisting of H and CH3; R2 is from the group consisting of H when R1 is CH3 and CH3 when R1 is H; and R3 is from the group of first radicals consisting of benzyl, phenethyl, disubstituted phenyl and trisubstituted phenyl. The substituted species are second radicals having positive lipophilicity selected from the group consisting of F, Cl, Br, and I.

This application is a Continuation-in-Part of application Ser. No.07/844,068, filed Mar. 2, 1992, now abandoned.

FIELD OF THE INVENTION

This invention relates to novel synthetic organic compounds havingsignificant central nervous system activity. More particularly, thisinvention relates to novel enaminone esters and enaminone amides and totheir methods of synthesis. Of particular interest are the cyclizedenaminone esters, which have markedly potent anticonvulsant activity,with only slight toxicity.

BACKGROUND OF THE INVENTION

Enaminones are a class of enamines, i.e., α,β-unsaturated aminesanalogous to enols. Enamines are Schiff bases, and are highly unstablein aqueous solutions. As such, enamines are used as potential prodrugs(agents which yield an amine on hydrolysis) providing a lipophilic, butacid-labile, carrier group to the active pharmacophore.

Enaminones are formed between a primary amine and a β-dicarbonylcompound, often referred to as vinylogous amides, in which the aminogroup is linked through a carbon-carbon double bond to a keto group.These compounds are well known; see, The Chemistry of Enamines, S. F.Dyke, Ed., Cambridge University Press, Cambridge, U.K. (1973); Enamines:Synthesis, Structure and Reactions, A. G. Cook, Ed., Marcel Dekker, NewYork (1969).

Enaminones are stabilized relative to enamines of monocarbonyl compoundsprobably due to intramolecular hydrogen bonding derived fromβ-diketones, such as acetylacetone, and such derivatives have foundusefulness as prodrugs of amines. The physicochemical properties, uses,and the hydrolysis of enamines under a variety of conditions are alsowell known: P. Y. Sollenberger, R. B. Martin, J. Am. Chem. Soc. (1970)Vol. 94, 4261-4270; J. K. Coward, T. C. Bruice, J. Am. Chem. Soc.(1969), Vol. 91, 5329-5339; K. Dixon, J. V. Greenhill, J. Chem. Soc.,Perkin Trans. 2 (1974), Vol. 2, 164-168; E. J. Stamhuis, W. Mass, J.Org. Chem. (1965), Vol. 30, 2156-2160; J. Kavalek, El-Bahei Said, V.Sterba, Collect. Czech. Chem. Commun. (1978) Vol. 43, 2732-2739; L. R.Fedor, Int. J. Pharm. (1984), Vol. 22, 197-205; J. D. Loosen, H.Bundgaard, Arch. Pharm. Chem. Sci., Ed. (1986), Vol. 14, 53-63; V. H.Naringrekar, V. J. Stella, J. Pharm. Sci. (1990), Vol. 79, 138-146.

Research related to enaminones has been generally limited to thestability of these compounds and their ability to yield the primary orsecondary amine on hydrolysis. Naringrekar and Stella recently reporteddisappointing results in the use of enaminones as prodrugs. There it wasreported that enaminones formed between amines and cyclic 1,3-dicarbonylcompounds were significantly more stable than acyclic analogs. Twoarticles did cite the potential use of enaminones for biologicalpurposes (G. Romussi, B. Parodi, G. Bignardi, G. Menozzi, P. Schenone,Il Farmaco-Ed. Sc. (1986) Vol. 41, 539-547; Y. Kase, M. Saita, K.Takahama, K. Masaki, T. Miyata, Jap. J. Pharmacol. (1974) Vol. 24,S127-S128). In the former reference, enaminones were evaluated forhypoglycemic effectiveness. However, the authors reported no interestingresults. In the latter reference, a Japanese abstract, the authorsreported MK 1-203(5,5-dimethyl-3-(o-chloro)phenylamino-2-(N-piperidinylmethyl)cyclohex-2-ene-1-one),and MK 1-907(5,5-dimethyl-3-(m-methoxy)phenyl-2-N-methyl-N-phenethylaminomethylcyclohex-2-ene-1-one),each of which were potent analgesics with morphine-like, as well asanticonvulsant and papaverine-like, actions. No further data wasprovided nor any subsequent information was cited from theirlaboratories. Significantly, none of the reports suggest the use ofenaminones as central nervous system agents, which may be effective fora variety of disorders, notably epilepsy, parkinsonism, Huntington'schorea and Alzheimer's disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show the reduction in seizure severity provided by anenaminone of the present invention in Corneal Kindled rats.

FIGS. 2A, 2B, and 2C give proposed "fingerprint" regions of the activesites in the enaminones of the present invention.

FIGS. 3A and 3B show the effect of substituted benzylamines andanilines.

SUMMARY OF THE INVENTION

Cyclic enaminone esters, ##STR2## are synthesized from beta hydroxyketoesters, ##STR3## which, in turn are synthesized by Michael addition of avinyl ketone to a malonic ester, followed by a Claisen condensation(Method A), or by a base-catalyzed condensation of crotonate ester andacetoacetate (Method B) to form, ##STR4## R=Alkyl; R¹,R² =H, H; H, CH₃ ;CH₃, CH₃ ; C6H₅, H

Method B was preferred, especially in the case of 3-penten-2-one, whichwas available in only 65% purity. 5-Methylcyclohexane-1,3-dione wasformed by the acid catalyzed decarboxylation of either methyl6-methyl-2-oxocyclohex-3-en-1-oate or the ethyl ester.

The beta hydroxyketo esters are refluxed with one equivalent of theappropriate amino compound under various conditions to provide thedesired product to produce enaminones ##STR5## where, R=H or an esterderivative such as COOCH₃ or COOC₂ H₅ ;

R¹ =H or CH₃ ;

R² =H when R¹ =CH₃ and CH₃ when R¹ =H;

R³ =heterocyclic radicals, benzyls, phenethyl, hydrazinos, phenyls orsubstituted, disubstituted or trisubstituted derivatives thereof,wherein the substitutions are from the group consisting of F, Cl, Br, I,C(CH₃)₃), CH₃, C₂ H₅, OCH₃, NO₂, NH₂, CF₃ and OCF₃, said substitutionshaving positive lipophilicity.

In the case of the hydrazino radicals, a much lower temperature wasemployed, due, most probably to the lower pk_(a) of the aniline (4.63for aniline) derivatives compared to the benzylamine analogues (9.33 forbenzylamine) (see, CRC Handbook of Chemistry and Physics, 65th Ed., R.C. Wease, Ed., CRC Press, Cleveland, Ohio (1985)) (Method D). Theenaminone esters can, in turn, be reacted with additional amine to yieldenaminone amides, either through the β-hydroxyketones (Method E) orthrough the intermediate enaminone esters (Method F).

DETAILED DESCRIPTION OF THE INVENTION

Melting points were determined on a Thomas Hoover capillary meltingpoint apparatus and are uncorrected. Observed boiling points were alsouncorrected. IR spectra were recorded on samples in Nujol, or as dilutedchloroform solutions in matched sodium chloride cells or neat with aPerkin-Elmer 1330 spectro-photometer. ¹ H NMR spectra were recorded on aGeneral Electric QE 300-MHz spectrometer in deuterated solvents usingtetramethylsilane as an internal reference. Elemental analyses (C, H, N,and halogen) were performed by Schwarzkopf Microanalytical Laboratory,Woodside, N.Y. Where analyses are indicated only by the symbols of theelements analytical results for the elements were within 0.4% of thetheoretical values. Experimental data for the enaminone compounds areprovided in Table I. Ethyl 4-hydroxy-6-methyl-2-oxo-cyclohex-3-en-1-oatewas prepared by Method B with comparable yields with Method A employedin the literature (T. A. Spencer, M. D. Newton, S. W. Baldwin, J. Org.Chem. (1964), Vol. 29, 787-789). 19 and 36 were prepared by Method Dwith comparable yields to those reported in the literature (K. Kotera,Yakugaku Zasshi (1960), Vol. 91, 1275-1278). Typical experimentsillustrating the general procedures for the preparation of theenaminones and intermediates are described below.

Methyl 4-hydroxy-6-methyl-2-oxocyclohex-3-en-1-oate (26) [R═CH₃, R¹ ═R²═CH₃ ]

Method A. To a freshly prepared solution of sodium (23 g, 1 g-atom) inmethanol (300 mL) was added dimethyl malonate (132 g, 1 mol) and themixture stirred on an ice bath for 15 minutes after the addition.Mesityl oxide (100 g, 1 mol) was added and the mixture stirred at roomtemperature for an additional 30 minutes. After refluxing for 12 hours,the white precipitate which separated was dissolved in a minimum amountof cold water, the aqueous solution was acidified with hydrochloric acid(400 mL of a 2.5M solution) and extracted with dichloromethane (4×200mL). The organic phase was dried (Na₂ SO₄), evaporated and the residuecrystallized from toluene to give the title compound. The methanolicfiltrate was evaporated to dryness and the residue dissolved in coldwater, acidified with hydrochloric acid and extracted withdichloromethane. The residue was recrystallized from toluene. Totalyield: 122.3 g (62%); mp 99°-101° C.; ¹ H NMR (CDCl₃) δ 1.14 (6H, d, 2 XCH₃), 2.20 (2H, AB system, diastereotropic CH₂), 3.14 (1H, s, CH ofcyclohexene ring), 3.70 (3H, s, OCH₃), 5.41 (1H, s, ═CH--), 9.35 (1H, brs, --OH). Anal. (C, H).

Method B. To a freshly prepared solution of sodium (17.8 g, 0.77 g-atom)in methanol (220 mL) was added methyl acetoacetate (89.7 g, 0.77 mol)over thirty minutes and the mixture stirred on an ice bath for anadditional fifteen minutes Ethyl crotonate (100 mL, 96% 0.77 mol) wasadded dropwise and the mixture stirred at room temperature for anadditional 30 minutes. After refluxing for 2 hours, the mixture wascooled and the precipitate treated as indicated in Method A. Yield: 57 g(40%) with identical constants as in Method A.

5-Methylcyclohexane-1,3-dione (26') (R═R¹ ═H; R² ═CH₃

Ethyl 4-hydroxy-6-methyl-2-oxocyclohex-3-3n-1-oate prepared by Method B,129 g (0.59 mol as the sodium enolate) was dissolved in 60 mL of water,118 mL of a 5M sodium hydroxide solution added and the mixture refluxedfor 1 hour. After cooling to room temperature, the mixture was acidifiedwith 90 mL of 5M sulfuric acid and extracted with dichloromethane (2×100mL). After washing with water, the organic layer was dried overmagnesium sulfate, the solvent removed under reduced pressure and theresidue distilled, bp 60° C. (0.3 mm), 33.5 g (44.9%), whichcrystallized on standing for one week. Recrystallized from toluene, mp71°-72° C. (Found: C, 66.4%; H, 8.0%. C₇ H₁₀ O₂ requires C, 66.6%; H,8.0%).

Methyl4-[(4'-chloro-2-pyridinyl)amino]-6-methyl-2-oxo-cyclohex-3-3n-1-oate(116)

Method C. To a solution of 26 (R=CH₃ ; R¹ =CH₃ ; R² =H) (5 g, 27 mmol)in 140 mL benzene was added 2-amino-5-chloropyridine (3.86 g, 30 mmol)and the mixture refluxed for 5 hours using a Dean-Stark water separator.During the reaction, 0.50 mL of water was collected. A light yellowprecipitate formed on cooling to room temperature (1.5 g, mp 197°-200°C.). The filtrate was evaporated under reduced pressure to yield anorange residue which was recrystallized from toluene to yield a secondcrop (1.95 g, mp 197°-198° C.). Further recrystallization of both cropsfrom toluene gave 116, in a total yield of 43% (3.45 g, mp 206°-208°C.); ¹ H NMR (DMSO-d₆) δ 0.96 (3H, d, J=4.89 Hz, CH₃), 2.24-3.58 (4H, m,CH₂ + 2CH of cyclohexene ring), 3.61 (3H, s, OCH₃), 6.82 (1H, s, ═CH--),7.03-8.32 (3H, m, pyridine ring), 9.57 (1H, s, --NH). Anal. (C, H, N,Cl).

Ethyl4-{[(4'-chloro-2'-benzoyl)phenyl]amino}-6-methyl-2-oxo-cyclohex-3-en-1-oate(133)

Method D. Compound 26 (R=C₂ H₅ ; R¹ =CH₃ ; R² =H) (1.98 g, 10 mmol) (2)was dissolved in absolute ethanol (150 mL) and2-amino-5-chlorobenzophenone (2.6 g, 11 mmol) added and the mixturerefluxed for 4 h. After evaporating the solution under reduced pressure,the residual red oil was triturated with ethyl acetate-petroleum ether(bp 37°-54° C.) and refrigerated until crystals were formed. Thecrystals were collected and recrystallized from ethyl acetate to yield133 (1.0 g, 24%, mp 154°-156° C.); ¹ H NMR (CDCl₃) 1.24 (3H, d, J=7.36Hz, CH₃), 1.25 (3H, t, J=6.25 Hz, CH₃), 1.63-3.54 (3H, m, CH₂ +CH ofcyclohexene ring), 4.19 (3H, m, CH₂ of ethyl group+CH of cyclohexenering), 7.16-7.56 (7H, m, C₆ H₅ +NH+vinyl H), 7.68-8.03 (3H, m, C₆ H₃ring). Anal. (C, H, N, Cl).

3-[(p-Chlorophenyl)amino]-5-methyl-2-cyclohexen-1-one (146)

Method D. 5-methyl-1,3-cyclohexanedione (5 g, 98%, 38.8 mmole) was addedto p-chloroaniline (5.5 g, 42.7 mmole) dissolved in a mixture of benzene(100 mL) and absolute ethanol (75 mL) and was refluxed for 4 hours.Evaporation of the solvents produced a yellow solid (2.43 g, 31%) whichwas recrystallized successively from toluene (mp 195°-196° C.) and amixture of ethyl acetate:acetone:methanol (2:2:1) and provided ananalytical sample (mp 198°-199.5° C.). Workup of the mother liquorsproduced additional 146 (5.80 g), providing an overall yield of 88%; ¹ HNMR (DMSO-d₆) δ 1.02 (3H, d, J=6.29 Hz, CH₃), 1.84-2.54 (5H, m,cyclohexene ring), 5.32 (1H, s, ═CH--), 7.16-7.48 (4H, m, C₆ H₄), 8.91(1H, s, --NH). Anal. (C, H, N, Cl).

3-(4'-Chlorophenyl)amino-2-cyclopentenone (151)

Method D. Cyclopentane-1,3-dione (5 g, 51 mmol) and p-chloro-aniline(7.15 g, 56 mmol) were dissolved in a mixture of 50 mL benzene and 75 mLabsolute ethanol and the mixture refluxed for 4 hours. On cooling andfollowing evaporation under reduced pressure, a solid residue formed.This residue was recrystallized from acetone-methanol-ethyl acetateproviding a yield of 8.83 g (84%), mp 215°-216° C.; ¹ H NMR (DMSO-d₆) δ2.21-2.76 (4H, m, cyclopentene ring), 5.45 (1H, s, ═C--), 7.21-7.43 (4H,m, C₆ H₄), 9.69 (1H, s, --NH). Anal (C, H, N, Cl).

Kinetic Hydrolysis. Compound 27 (5.9 mg), was dissolved in 95% ethanoland diluted to 50 mL with ethanol. This solution was 4.0×10⁻⁵ M.Phosphate buffer, pH 7.4 and water were used in this study. Allexperiments were performed in triplicate. A volume of the stock ethanolsolution of 1 (0.2 mL), was diluted with the appropriate solvent to make1 mL of solution. Each mixture was sealed in a Teflon capped reactionvial and incubated at 37° C. for the same time periods as indicated inthe ip rat toxicity study (Tables X and X-A). After each time period,the vials were removed from the incubator and quenched at -80° C. untilready for analysis. Initial scan (t=0 h) indicated a λ max at 311 nm for27. The potential hydrolysis products, methyl4-hydroxy-6-methyl-2-oxocyclohex-3-en-1-oate had a λ max of 277 nm andp-chloroaniline had a λ max of 232 nm under the same conditions. Afterall samples were incubated, the UV spectra was taken from 190-500 nmusing the respective solvent as a blank. The results were plotted interms of absorbance v, time of incubation and the absorbance values. Theaverage absorbance values for 27 in aqueous media was 0.929 (range0.789-1.069), while in pH 7.4 buffer the average value was 1.112 (range0.983-1.240). However, the wavelength did not change from 311 nm.Statistical analysis revealed that these individual differences were notsignificant (p<0.05).

Enzymatic Hydrolysis. A solution of (4×10⁻⁵ M), prepared as indicatedabove, Tris buffer (0.01M, pH 8.0) and esterase (EC 3.1.1.1, 200 unitsper mg, 19 mg dissolved in Tris buffer and diluted to 10 mL) wasemployed. The above assay was repeated in 1176Xtriplicate 0.2 mL ofstock solution, 1 mL buffer and 0.1 mL of enzyme solution and theincubation carried out at 37° C. for each time period (0.25, 0.5, 1, 2,4, 8 and 24 h). The blank (time=0 h) contained 0.2 mL of stock solutionand 1.1 mL buffer, but no enzyme. After each time period, the sampleswere quenched with 1 mL methylene chloride and frozen at -80° C. untilready for assay. In a preliminary experiment, 27 and 146, each 4×10⁻⁵ Min methylene chloride were analyzed by UV spectroscopy. The λ max for 27were 301.5 and 226.7 nm, while the λ max for 146 were 301.5 and 229.4nm. The latter wavelength differentiation was employed in the subsequentassay. Each sample was thawed, and the methylene chloride layer scannedin the UV region.

Table I sets forth 75 enaminones prepared according to the recipes setout above. Table II sets forth the analytical results for compoundsprepared in Table I. For those compounds not shown on Table II, theanalytical results obtained were within ±0.4% of the theoretical values.

                                      TABLE I                                     __________________________________________________________________________    Physical Properties of Enaminones.sup.a                                                                    mp, °C..sup.b                                                          or bp,                                           No.                                                                              R        R.sup.1                                                                          R.sup.2                                                                          R.sup.3    °C. (mm)                                                                      formula                                   __________________________________________________________________________     11                                                                              CONCH.sub.2 C.sub.6 H.sub.5                                                            C.sub.6 H.sub.5                                                                  H  CH.sub.2 C.sub.6 H.sub.5                                                                 219-220.sup.g                                                                        C.sub.27 H.sub.26 N.sub.2 O.sub.2          12                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.5                                                                 154-155.sup.d                                                                        C.sub.16 H.sub.19 NO.sub.3                 13                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.2 C.sub.6 H.sub.5                                                                 138-139.sup.d                                                                        C.sub.17 H.sub.21 NO.sub.3                 14                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         130-131.sup.f                                                                        C.sub.18 H.sub.23 NO.sub.3                 15                                                                              CON(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                    CH.sub.3                                                                         H  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         171-172.sup.d                                                                        C.sub.24 H.sub.28 N.sub.2 O.sub.2          16                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-Cl)                                                          173-174.sup.g                                                                        C.sub.16 H.sub.18 NO.sub.3 Cl              17                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-CH.sub.3)                                                    160-163.sup.g                                                                        C.sub.17 H.sub.21 NO.sub.3                 18                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-CO.sub.2 H)                                                  231-235 d..sup.g                                                                     C.sub.17 H.sub.19 NO.sub.5                 19                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.2 C.sub.6 H.sub.5                                                                 124-127.sup.g                                                                        C.sub.15 H.sub.19 NO                       20                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-NO.sub.2)                                                    174-176.sup.i                                                                        C.sub.16 H.sub.18 N.sub.2 O.sub.5          21                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-F)                                                           174-176.sup.g                                                                        C.sub.17 H.sub.18 NO.sub.3 F               22                                                                              CONHCH.sub.2 C.sub.6 H.sub.5                                                           CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.5                                                                 192-193.sup.g                                                                        C.sub.22 H.sub.24 N.sub.2 O.sub.2          23                                                                              CONHC.sub.6 H.sub.5                                                                    CH.sub.3                                                                         H  C.sub.6 H.sub.5                                                                          243-244.sup.j                                                                        C.sub.20 H.sub.20 N.sub.2 O.sub.2          24                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.5                                                                          141-144.sup.f                                                                        C.sub.15 H.sub.17 NO.sub.3                 25                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  NHC.sub.6 H.sub.5                                                                        167-167.5.sup.k                                                                      C.sub.15 H.sub.18 N.sub.2 O.sub.3          26                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-C.sub.2 H.sub.5)                                                      152-157.sup.f                                                                        C.sub.17 H.sub.21 NO.sub.3                 27                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-Cl)                                                                   178-180.sup.f                                                                        C.sub.15 H.sub.16 NO.sub.3 Cl              28                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-CH.sub.3)                                                             144-146.sup.f                                                                        C.sub.16 H.sub.19 NO.sub.3.H.sub.2 O       29                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-NO.sub.2)                                                             186-187.sup.f                                                                        C.sub.15 H.sub.16 N.sub.2 O.sub.5          30                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.3 (2'-OCH.sub.3,-                                               5'-CH.sub.3)                                                                             160.5-161.5.sup.f                                                                    C.sub.17 H.sub.21 NO.sub.4                 31                                                                              CO.sub. 2 CH.sub.3                                                                     CH.sub.3                                                                         H  C.sub.6 H.sub.3 (2',5'-(OCH.sub.3).sub.2                                                 134-135.sup.f                                                                        C.sub.17 H.sub.21 NO.sub.5                 32                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-COOH)                                                                 222-226 d..sup.g                                                                     C.sub.16 H.sub.17 NO.sub.5                 33                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  N(CH.sub.2).sub.2 O                                                                      200-202.sup.k                                                                        C.sub.13 H.sub.20 N.sub.2 O.sub.4          34                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  N(CH.sub.2).sub.2 O                                                                      207-212.sup.g                                                                        C.sub.13 H.sub.20 N.sub.2 O.sub.4          35                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-OH)                                                                   182-183.sup.f                                                                        C.sub.15 H.sub.17 NO.sub.3                 36                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.5                                                                          181-183.sup.f                                                                        C.sub.14 H.sub.17 NO                      108                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  CH(CH.sub.3)C.sub.6 H.sub.5)                                                             190-193.sup.k                                                                        C.sub.17 H.sub.21 NO.sub.3                109                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         116-118.sup.k                                                                        C.sub.17 H.sub.21 NO.sub.3                110                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  (CH.sub.2).sub.3 C.sub.6 H.sub.5                                                         163-164.sup.l                                                                        C.sub.18 H.sub.23 NO.sub.3                111                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  (CH.sub.2).sub.4 C.sub.6 H.sub.5                                                         90-92.sup.m                                                                          C.sub.19 H.sub.25 NO.sub.3                112                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-F)                                                                    161-164.sup.n                                                                        C.sub.15 H.sub.16 NO.sub.3 F              113                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-Br)                                                                   188-190.sup.o                                                                        C.sub.15 H.sub.16 NO.sub.3 Br             114                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-C(CH.sub.3).sub.3)                                                    221-222.sup.n                                                                        C.sub.19 H.sub.25 NO.sub.3                115                                                                              CH.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-CF.sub.3)                                                             169-170.sup.m                                                                        C.sub.16 H.sub.16 NO.sub.3 F.sub.3        116                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         H                                                                                 ##STR6##  206-208.sup.k                                                                        C.sub.14 H.sub.15 N.sub.2 O.sub.3         117                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.5                                                                          168-169.sup.d                                                                        C.sub.16 H.sub. 19 NO.sub.3               118                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-NO.sub.2)                                                             178-179.sup.m                                                                        C.sub.16 H.sub.18 N.sub.2 O.sub.5         119                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-Cl)                                                                   141-143.sup.d                                                                        C.sub.16 H.sub.18 NO.sub.3 Cl             120                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-C(CH.sub.3).sub.3)                                                    170-171.sup.m                                                                        C.sub.20 H.sub.27 NO.sub.3                121                                                                              CO.sub.2 CH.sub.3                                                                      CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-CF.sub.3)                                                             158-159.sup.m                                                                        C.sub.17 H.sub.18 NO.sub.3 F.sub.3        122                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-Cl)                                                                   161-163.sup.d                                                                        C.sub.16 H.sub.18 NO.sub.3 Cl             123                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-Br)                                                                   151-154.sup.d                                                                        C.sub.16 H.sub.18 NO.sub.3 Br             124                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-F)                                                                    150-151.5.sup.d                                                                      C.sub.16 H.sub.18 NO.sub.3 F              125                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-CH.sub.3)                                                             134.5-135.5.sup.m                                                                    C.sub.17 H.sub.21 NO.sub.3                126                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-C.sub.2 H.sub.5)                                                      148.5-150.sup.m                                                                      C.sub.18 H.sub.23 NO.sub.3                127                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-NO.sub.2)                                                             173-175.sup.d                                                                        C.sub.16 H.sub.18 N.sub.2 O.sub.5         128                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.3 (2',5'-(OCH.sub.3).sub.2)                                                137-138.sup.d                                                                        C.sub.18 H.sub.23 NO.sub.5                129                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.5                                                                          155-158.sup.n                                                                        C.sub.16 H.sub.19 NO.sub.3                130                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-C(CH.sub.3).sub.3)                                                    165.5-166.sup.d                                                                      C.sub.20 H.sub.27 NO.sub.3                131                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-CF.sub.3)                                                             184.5-186.sup.d                                                                      C.sub.17 H.sub.18 NO.sub.3 F.sub.3        132                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H  CH.sub.2 C.sub. 6 H.sub.5                                                                134.5-135.5.sup.m                                                                    C.sub.17 H.sub.21 NO.sub.3                133                                                                              CO.sub.2 C.sub.2 H.sub.5                                                               CH.sub.3                                                                         H                                                                                 ##STR7##  153-154.5.sup.m                                                                      C.sub.23 H.sub.22 NO.sub.4 Cl             134                                                                              CONHCH.sub.2 C.sub.6 H.sub.4                                                           CH.sub.3                                                                         H  CH.sub.2 C.sub.6 H.sub.4 (p-F)                                                           183-184.sup.p                                                                        C.sub.22 H.sub.22 N.sub.2 O.sub.2 F          (p-F)                                                                      137                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-Cl)                                                                   208-210.sup.p                                                                        C.sub.14 H.sub.16 NOCl                    138                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-NO.sub.2)                                                             242-244.sup.p                                                                        C.sub.14 H.sub.16 N.sub.2 O.sub.3         139                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-CH.sub.3)                                                             203-204.sup.q                                                                        C.sub.15 H.sub.19 NO                      140                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-C.sub.2 H.sub.5)                                                      201-202.5.sup.q                                                                      C.sub.16 H.sub.21 NO                      141                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-OCH.sub.3)                                                            189-191.sup.d                                                                        C.sub.15 H.sub.19 NO.sub.2                142                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-NH.sub.2)                                                             211.5-212.5.sup.q                                                                    C.sub.14 H.sub.18 N.sub.2 O               143                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-C(CH.sub.3).sub.3)                                                    206-208.sup.n                                                                        C.sub.18 H.sub.25 NO                      144                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         C.sub.6 H.sub.4 (p-CF.sub.3)                                                             240.5-241.5.sup.n                                                                    C.sub.15 H.sub.16 NOF.sub.3               145                                                                              H        CH.sub.3                                                                         CH.sub.3                                                                         (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         121-123.sup.d                                                                        C.sub.16 H.sub.21 NO                      146                                                                              H        CH.sub.3                                                                         H  C.sub.6 H.sub.4 (p-Cl)                                                                   198-199.5.sup.?                                                                      C.sub.13 H.sub.14 NOCl                    147                                                                              H        H  H  C.sub.6 H.sub.4 (p-Cl)                                                                   190-191.5.sup.l                                                                      C.sub.12 H.sub.12 NOCl                    148                                                                              H        H  H  CH.sub.2 C.sub.6 H.sub.5                                                                 125-127.sup.s                                                                        C.sub.13 H.sub.15 NO                      149                                                                              H        H  H  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         93.5-95.sup.e                                                                        C.sub.14 H.sub.17 NO                      150                                                                              H        H  H  C.sub.6 H.sub.4 (p-C(CH.sub.3).sub.3)                                                    185-187.sup.n                                                                        C.sub.16 H.sub.21 NO                      151                                                                              H        H  H  C.sub.6 H.sub.4  (p-CF.sub.3)                                                            203-204.sup.d                                                                        C.sub.13 H.sub.12 NOF.sub.3               152                                                                              H        H  H  C.sub.6 H.sub.4 (p-Cl)                                                                   216-217.sup.r                                                                        C.sub.12 H.sub.11 NOCl                    153                                                                              H        H  H  CH.sub.2 C.sub.6 H.sub.5                                                                 139-141.5.sup.g                                                                      C.sub.13 H.sub.15 NO                      154                                                                              H        H  H  (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         136-138.sup.?                                                                        C.sub.14 H.sub.17 NO                      __________________________________________________________________________     .sup.a The infrared and .sup.1 H NMR spectra were consistent with assigne     structures. .sup.b Recrystallization solvents as indicated. .sup.c            EtOAcpetroleum ether (80-100° C.). .sup.d EtOAc. .sup.e                EtOAcligroine (70-90° C.). .sup.f 2Propanol. .sup.g Methanol.          .sup.i MethanolH.sub.2 O. .sup.j Toluenemethanol. .sup.k Toluene. .sup.l      EtOAc/EtOH. .sup.m EtOAc/Petroleum ether (bp 38-54° C.). .sup.n        EtOAc/Me.sub.2 CO. .sup.o 2PrOH/Me.sub.2 CO. .sup.p MeOH/Me.sub.2 CO.         .sup.q EtOH. .sup.r EtOAc:Me.sub.2 CO:MeOH (2:2:1). .sup.s 2PrOH.        

                                      TABLE II                                    __________________________________________________________________________    Analyses of Enaminones                                                             Empirical                                                                              Elements                                                        Compd.                                                                             Form     Analyzed                                                                            Calculated Found                                          __________________________________________________________________________    11   C.sub.27 H.sub.26 N.sub.2 O.sub.2                                                      C, H, N                                                                             79.02, 6.34, 6.83                                                                        78.83, 6.44, 6.74                              12   C.sub.16 H.sub.19 NO.sub.3                                                             C, H, N                                                                             70.33, 6.96, 5.13                                                                        70.60, 7.10, 5.10                              13   C.sub.17 H.sub.21 NO.sub.3                                                             C, H, N                                                                             71.08, 7.32, 4.87                                                                        71.34, 7.26, 4.95                              14   C.sub.18 H.sub.23 NO.sub.3                                                             C, H, N                                                                             71.76, 7.64, 4.65                                                                        71.87, 7.71, 4.61                              15   C.sub.24 H.sub.28 N.sub.2 O.sub.2                                                      C, H, N                                                                             76.60, 7.45, 7.45                                                                        76.50, 7.60, 7.50                              16   C.sub.16 H.sub.18 NO.sub.3 Cl                                                          C, H, N, Cl                                                                         62.49, 5.91, 4.55, 11.52                                                                 62.32, 5.91, 4.50, 11.36                       17   C.sub.17 H.sub.21 NO.sub.3                                                             C, H, N                                                                             71.04, 7.38, 7.84                                                                        70.83, 7.34, 4.76                              18   C.sub.17 H.sub.19 NO.sub.5                                                             C, H, N                                                                             64.33, 6.05, 4.41                                                                        64.60, 6.02, 4.44                              19   C.sub.15 H.sub.19 NO                                                                   C, H, N                                                                             78.55, 8.37, 6.11                                                                        78.38, 8.23, 5.99                              20   C.sub.16 H.sub.18 N.sub.2 O.sub.5                                                      C, H, N                                                                             60.36, 5.71, 8.80                                                                        60.56, 5.66, 8.71                              21   C.sub. 16 H.sub.17 NO.sub.3 F                                                          C, H, N, F                                                                          66.18, 5.91, 4.83, 6.54                                                                  65.94, 6.03, 4.75, 6.80                        22   C.sub.22 H.sub.24 N.sub.2 O.sub.2                                                      C, H, N                                                                             75.82, 6.96, 8.04                                                                        75.67, 7.00, 8.11                              23   C.sub.20 H.sub.20 N.sub.2 O.sub.2                                                      C, H, N                                                                             74.96, 6.30, 8.74                                                                        75.06, 6.25, 8.60                              24   C.sub.15 H.sub.17 NO.sub.3                                                             C, H, N                                                                             69.47, 6.62, 5.40                                                                        69.25, 6.40, 5.27                              25   C.sub.15 H.sub.18 N.sub.2 O.sub.3                                                      C, H, N                                                                             65.66, 6.63, 10.21                                                                       65.82, 6.74, 10.45                             26   C.sub.17 H.sub.21 NO.sub.3                                                             C, H, N                                                                             71.04, 7.38, 4.87                                                                        70.83, 7.14, 4.85                              27   C.sub.15 H.sub.16 NO.sub.3 Cl                                                          C, H, N, Cl                                                                         61.32, 5.50, 4.77, 12.07                                                                 61.05, 5.42, 4.81, 11.82                       28   C.sub.16 H.sub.19 NO.sub..sub.3.H.sub.2 O                                              C, H, N                                                                             65.95, 6.59, 4.80                                                                        66.04, 6.55, 4.84                              29   C.sub.15 H.sub.16 N.sub.2 O.sub.5                                                      C, H, N                                                                             59.20, 5.31, 9.21                                                                        59.00, 5.12, 8.95                              30   C.sub.17 H.sub.21 NO.sub.4                                                             C, H, N                                                                             67.30, 6.99, 4.62                                                                        67.15, 6.89, 4.53                              31   C.sub.17 H.sub.21 NO.sub.5                                                             C, H, N                                                                             63.92, 6.64, 4.39                                                                        64.02, 6.89, 4.25                              32   C.sub.16 H.sub.17 NO.sub.5                                                             C, H, N                                                                             63.35, 5.66, 4.62                                                                        63.18, 5.43, 4.79                              33   C.sub.13 H.sub.20 N.sub.2 O.sub.4                                                      C, H, N                                                                             58.18, 7.53, 10.44                                                                       58.23, 7.35, 10.17                             34   C.sub.13 H.sub.20 N2O.sub.4                                                            C, H, N                                                                             58.18, 7.53, 10.44                                                                       58.14, 7.65, 10.49                             35   C.sub.15 H.sub.17 NO.sub.3                                                             C, H, N                                                                             65.43, 6.24, 5.09                                                                        65.37, 6.32, 5.06                              36   C.sub.14 Hl7NO                                                                         C, H, N                                                                             78.08, 7.97, 6.51                                                                        77.73, 7.66, 6.37                              __________________________________________________________________________

NMR results at 300 MHz of the enaminones were consistent with theassigned structures. Of particular interest was the assignment of themethoxy groups in methyl 4-(2',5'-dimethoxy)-phenylamino-6-methyl-2-oxo-cyclohex-3-en-1-oate, 31. Thechemical shifts (δ ppm) for the carbomethoxy, 2'-methoxy, and 5'-methoxyprotons occurred at 3.81, 3.84 and 3.78, respectively.

To determine whether the condensation of cyclic 1,3-dicarbonyl analogswith benzylamine, substituted benzylamines, aniline, substitutedanilines and hydrazines produced stable, water-soluble, highly potentand non-toxic compounds possessing anticonvulsant activity comparable tothose agents currently commercially available, compounds produced asdescribed were assayed for anticonvulsant activity by the AntiepilepticDrug Development (ADD) Program, Epilepsy Branch, Neurological DisordersProgram, National Institute of Neurological and Communicative Disordersand Stroke, National Institutes of Health.

The first phase of the ADD Program involved performing tests on maleCarworth Farms #1 mice. Each novel enaminone compound was tested atleast 3 dose levels (30, 100, 300 mg/kg) as described (AnticonvulsantScreening Project, Antiepileptic Drug Development Program, NationalInstitutes of Health, DHEW Publ. (NIH) (U.S.) (1978), NIH 78-1093; R. J.Porter, J. J. Cereghino, G. D. Gladding, B. J. Hessie, H. J. Kupferberg,B. Scoville, B. G. White, Cleveland Clin. Q. (1984), Vol. 51, 293-301;R. L. Krall, J. K. Penry, B. G. White, H. J. Kupferberg, E. A. Swinyard,Epilepsia (1978), Vol. 19, 400-422). The vehicle used to solubilize eachcompound, the tests undertaken and related data are indicated on thetest results form found in the subsequent pages of this application.Three tests were performed:

1. MES--Electroshock Seizure Test

Maximal electroshock seizures are elicited with a 60-cycle alternatingcurrent of 50 mA intensity (5-7 times that necessary to elicit minimalelectroshock seizures) delivered via corneal electrodes for 0.2 seconds.A drop of 0.9% saline is instilled in the eye prior to application ofthe electrodes in order to prevent the death of the animal. Abolition ofthe hind limb tonic extension component of the seizure is defined asprotection and results are expressed as the number of animalsprotected/the number of animals tested.

2. sc Met--Subcutaneous Pentylenetetrazol (Metrazol ^(R)) Seizure Test

Eighty-five mg/kg of pentylenetetrazol, which induces seizures in morethan 95% of mice) is administered as a 0.5% solution subcutaneously inthe posterior midline. The animal is observed for 30 minutes. Failure toobserve even a threshold seizure (a single episode of clonic spasms ofat least 5 seconds duration) is defined as protection and the resultsare expressed as the number of animals protected/the number of animalstested.

3. Tox--Toxicity

The rotorod test is used to elevate neurotoxicity. The animal is placedon a 1 inch diameter knurled plastic rod rotating at 6 rpm. Normal micecan remain on a rod rotating at this speed indefinitely. Neurologictoxicity is defined as the failure of the animal to remain on the rodfor 1 minute and the results are expressed as the number of animalsprotected/the number of animals tested.

                  TABLE III                                                       ______________________________________                                        Anticonvulsant Screening Project (ASP): Phase I Test Results                            Activity                                                            Dose,       MES.sup.a  scMet.sup.b                                                                              Tox.sup.c                                   Compound                                                                              mg/kg   30 min  4 h  30 min                                                                              4 h  30 min                                                                              4 h                             ______________________________________                                         12     100     2/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1.sup.e                                                                             0/1.sup.d                                                                          0/1   0/1.sup.d                                                                          3/4   0/2                              13     300     1/1     0/1  0/1   0/1.sup.d                                                                          1/4   0/2                              14     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     0/1.sup.d                                                                          0/1   0/1  1/4   0/2                              15     300     0/1     1/1  0/1   0/1  0/4   0/2                              16     300     1/1     1/1  1/1   0/1  0/4   0/2                                                          (0/4)      (0/4)                                  19     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     1/1.sup.d                                                                          0/1   0/1  1/4   0/2                              21     300     0/1     1/1  0/1   0/1  0/4   0/2                              25     300     1/1     0/1  1/1   0/1  0/4   0/2                                                          (0/4)      (0/4)                                  26     100     2/3     0/3  0/1   0/1  0/8   0/4                              27     100     3/3     0/3  0/1   0/1  1/8   0/4                                     300     1/1     1/1  0/1   0/1  4/4   0/2                              28      30     0/1     0/1  1/1   0/1  0/4   0/2                                                          (0/4)      (0/4)                                         300     1/1.sup.d                                                                             0/1.sup.d                                                                          0/1   0/1  2/4   0/2                              29     100     0/3     0/3  1/1   0/1  0/8   0/4                                                          (0/4)      (0/4)                                  31     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     0/1  0/1   0/1  0/4   0/2                              36     100     2/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     0/1  0/1   0/1  0/4   0/2                             109     100     2/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1  0/1   0/1  4/4   2/2                             112     100     2/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  0/1   0/1  4/4   0/2                             113     100     3/3     3/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  2/5   0/1  0/4   0/2                             115     100     3/3     1/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  2/5   0/1  0/4   0/2                             116     100     2/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1.sup.f                                                                          1/1   0/1  1/4   0/2                                                          (3/4)      (0/4)                                 118     300.sup.g                                                                             0/1     1/1  0/1   0/1  0/4   0/2                             119     100     3/3     3/3  0/1   0/1  8/8   2/4                                     300.sup.e                                                                             1/1     1/1  1/1   1/1  4/4.sup.h                                                                           2/2                             121     100     3/3     3/3  0/1   0/1  2/8   4/4                                     300     1/1     1/1  0/1   0/1  4/4   2/2                             122     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  1/1   0/1  4/4   0/2                                                          (2/4)      (4/4)                                 123     100     3/3     2/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  0/1   0/1  0/4   0/2                             124     100     3/3     0/3  0/1   0/1  1/8   0/4                                     300     1/1     0/1  1/1   0/1  4/4   0/2                                                          (2/4)                                            125     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1  0/1   0/1  0/4   0/2                             126     300.sup.e                                                                             1/1     0/1  0/1   0/1  0/4   0/2                             127     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1  1/1   0/1  4/4   0/2                                                          (2/4)      (4/4)                                 128     300.sup.e                                                                             1/1     0/1  0/1   0/1  0/4   0/2                             130     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1  0/1   0/1  0/4   0/2                             131     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  0/1   0/1  0/4   0/2                             138     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     0/1  0/1   0/1  0/4   0/2                             140     300.sup.g                                                                             0/1     1/1  0/1   0/1  0/4   0/2                             142     100     0/3     1/3  0/1   0/1  0/8   0/4                                     300.sup.e                                                                             1/1     1/1  0/1   0/1  0/4   0/2                             143     100     0/3     0/3  1/5   0/1  0/8   0/4                                     300     0/1     0/1  1/5   0/1  0/4   0/2                             144     100     0/3     2/3  0/1   0/1  0/8   0/4                                     300     0/1     0/1  1/1   0/1  0/4   0/2                             145     300.sup.e                                                                             1/1     0/1  0/1.sup.i                                                                           0/1  4/4   0/2                             146     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1.sup.f                                                                             1/1.sup.f                                                                          2/5   0/1  2/4   2/2                             147     100     3/3     0/3  0/1   0/1  8/8   0/4                                     300.sup.e                                                                             1/1     1/1  0/1   0/1  .sup. 4/4.sup.h                                                                     1/2                             148     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     0/1  0/1   0/1  .sup. 4/4.sup.j                                                                     0/2                             149     100     3/3     0/3  0/1   0/1  4/8   0/4                                     300     1/1     0/1  .sup. 0/0.sup.k                                                                     0/1  .sup. 4/4.sup.h                                                                     1/2.sup.l                       150     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     1/1  3/5   0/1  4/4   0/2                             151     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     1/1  0/1   0/1  4/4   0/2                             152     100     1/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1.    0/1  0/1   0/1  0/4   0/2                             153     100     3/3     0/3  0/1   0/1  0/8   0/4                                     300     1/1     1/1  0/1   0/1  .sup. 4/4.sup.j                                                                     0/2                             154     300     1/1     0/1  0/1   0/1  .sup. 4/4.sup.j                                                                     0/2                             ______________________________________                                         .sup.a Maximal electroshock test (number of animals protected/number of       animals tested).                                                              .sup.b Subcutaneous pentylenetetrazol test.                                   .sup.c Toxicity (number of animals exhibiting toxicity/number of animals      tested). Results in parentheses are the results of a second trial.            .sup.d Toxic at 30 min. Other compounds in Table I were inactive at doses     up to 300 mg/kg.                                                              .sup.e 0/2 MES animals dead after 24 h at 300 mg/kg.                          .sup.f Toxic at 30 min.                                                       .sup.g 0/1 MES animals dead after 24 h at 300 mg/kg.                          .sup.h Unable to hold onto retorod.                                           .sup.i Continuous seizure activity followed by death.                         .sup.j Unable to grasp rotorod.                                               .sup.k Died during test without having seizure.                               .sup.l Toxic at 4 h.                                                          .sup.m One unable to grasp rotorod.                                           .sup.n Exhibited sweating and hyperactivity.                                  .sup.o Died.                                                             

                  TABLE IV                                                        ______________________________________                                        Anticonvulsant Screening Project (ASP): Phase I Test Results                                 ASP                                                            COMPOUND       Classification.sup.d                                           ______________________________________                                         12            1                                                               13            2                                                               14            1                                                               15            2                                                               16            2                                                               19            1                                                               21            2                                                               25            2                                                               26            1                                                               27            1                                                               28            1                                                               29            1                                                               31            1                                                               36            1                                                              109            1                                                              112            1                                                              113            1                                                              115            1                                                              116            1                                                              118            2                                                              119            1                                                              121            1                                                              122            1                                                              123            1                                                              124            1                                                              125            1                                                              126            2                                                              127            1                                                              128            2                                                              130            1                                                              131            1                                                              138            1                                                              140            2                                                              142            1                                                              143            1                                                              144            1                                                              145            2                                                              146            1                                                              147            1                                                              148            1                                                              149            1                                                              150            1                                                              151            1                                                              152            1                                                              153            1                                                              154            2                                                              ______________________________________                                         .sup.d The classifications are as follows: 1, anticonvulsant activity at      100 mg/kg or less; 2, anticonvulsant activity at doses greater than 100       mg/kg.                                                                   

The results of the Phase I tests for those compounds which displayedanticonvulsant activity are presented on Table III. Table IV presentsthe results of the Phase I tests in which the compounds are classifiedaccording to their anticonvulsant activity. Because compounds 16, 25 and28 gave spurious results in the scMet evaluation, testing of thesecompounds was halted.

As a result of these tests, compounds 12, 13, 27, 31 and 36 wereadvanced to the Phase II testing regimen. In the second phase of the ADDprogram protocol, estimates of anticonvulsant activity and neurotoxicityare quantified. The median effective dose (ED50) in the MES, sc Met, androtorod test is determined. In the case of a compound with apparentactivity in only one anticonvulsant test, testing is carried out in theother up to, and in some cases beyond, doses which produce neurologicaldeficit. Compounds which fail to produce minimal neurological deficitare tested whenever possible to doses ten times their lowestanticonvulsant ED50. Determination of the MES and sc Met ED50 is carriedout at the time of peak effect in the tests, except when preliminarytesting indicates that activity occurs at another time. The rotorod ED50is determined at the time of the peak neurologic deficit.

The results of the Phase II tests are shown in Table V. Also included isdata for several currently marketed anticonvulsants for comparison. Theprotective indices for 12 (7.73) and 27 (9.72) compare favorably withphenytoin (9.59) and both far surpass valproate (1.90). It should alsobe noted that the criteria for the evaluation of toxicity for the threecommercial compounds is not the same as for the compounds synthesizedherein. Whereas compounds 12, 13, 27 and 36 were evaluated for theability of the test animals to remain on the rotorod, the commercialproducts were based on the onset of ataxia. It should be noted that noneof the compounds reported displayed ataxia.

                                      TABLE V                                     __________________________________________________________________________    Phase II Quantification Data                                                                              TPE.sup.e                                         Compound                                                                              MES, ED50.sup.a,b                                                                      TD50.sup.a,c                                                                       PI, MES.sup.d                                                                       activity                                                                          toxicity                                      __________________________________________________________________________    12       64.70   >500 7.73  0.5 1                                                     (41.41-88.86)                                                                          (nd)                                                         13      131.90   >500 3.79  0.5 1                                                     (92.33-188.5)                                                                          (nd)                                                         27       26.20   254.78                                                                             9.72  0.5 2                                                     (16.57-40.36)                                                                          (202.15-                                                                      321.81)                                                      36      109.38   232.58                                                                             2.13  0.5 0.5                                                    (87.91-124.31)                                                                        (199.94-                                                                      273.09)                                                      phenytoin                                                                              9.04    86.7 9.59  2   2                                                     (7.39-10.6)                                                                            (80.4-                                                                        96.1)                                                        carbamazepine                                                                         15.4     217  14.1  0.5 0.5                                                   (12.4-17.3)                                                                            (131-                                                                         270)                                                         valproate                                                                             665      1264 1.90  1   2                                                     (605-728)                                                                              (800-                                                                         2250)                                                        __________________________________________________________________________     .sup.a ED50 and TD50 values are in milligrams/kilogram of test drug           delivered intraperitoneally (ip).                                             .sup.b Measured at time of peak effect.                                       .sup.c Measured at time of peak neurologic deficit.                           .sup.d PI = protective index (TD50/ED50).                                     .sup.e Time of peak effect. Numbers in parentheses are 95% confidence         interval.                                                                     nd = not determined.                                                     

                  TABLE V-A                                                       ______________________________________                                        Additional Phase II Data                                                                 Dose,   Time,                                                      Compound   mg/kg   h.         MES.sup.a                                                                           Tox.sup.b                                 ______________________________________                                        118        100     2.00       0/2   0/2                                                          3.00       0/2   0/2                                       121         3      0.50       0/4   0/4                                                   10     0.50       0/4   0/4                                       122         3      0.50       0/4   0/4                                                   10     0.50       1/4   0/4                                       126        100     0.25       2/2   0/2                                                          1.00       0/2   0/2                                       127         3      0.50       0/4   0/4                                                   10     0.50       0/4   0/4                                       128        100     0.25       0/2   0/2                                                          1.00       0/2   0/2                                       140        100     2.00       0/2   0/2                                                          3.00       0/2   0/2                                       142        100     0.25       1/2   0/2                                                          1.00       1/2   0/2                                       145        100     0.25       0/2   0/2                                                          1.00       0/2   0/2                                       154        100     0.25       2/2   0/2                                                          1.00       0/2   0/2                                       ______________________________________                                         .sup.a Maximal electroshock test (refer to Table III for definition).         .sup.b Rotorod toxicity (refer to Table III for definition).                  .sup.c Inactive in scMet evaluations during the same time periods.       

Due to the need for more rapid evaluation of the enaminones, a specialintraperitoneal (ip) time of peak effect and toxicity evaluation wasperformed in mice on 116, 122, 123, 125, 130 and 131, which showedanti-MES protecting ability in phase I. These results are shown in TableVI. Table VII shows MES activity evaluated at 10 mg/kg and toxicitymonitored at 100 mg/kg compounds 113 and 115, which were subsequentlyevaluated at the same dosage in rats. The ip ED 50 and TD 50 for 113 and115 are shown in Table VIII.

                  TABLE VI                                                        ______________________________________                                        Intraperitoneal (ip) time of peak effect and toxicity of                      Compounds 116, 122, 123, 125, 130 and 131.                                              Time,       MES.sup.a                                                                              Tox.sup.a                                      Compound  h           10 mg/kg 100 mg/kg                                      ______________________________________                                        116       0.25        3/4      .sup. 1/8.sup.b                                          0.50        4/4      .sup. 6/8.sup.b                                          1.00        2/4      .sup. 6/8.sup.b                                          2.00        0/4      0/8                                                      4.00        0/4      0/8                                                      6.00        nd       0/8                                                      24.00       nd       0/8                                            122       0.25        3/4      1/8                                                      0.50        3/4      3/8                                                      1.00        4/4      3/8                                                      2.00        1/4      3/8                                                      4.00        1/4      3/8                                                      6.00        nd       0/8                                                      24.00       nd       0/8                                            123       0.25        3/4      .sup. 0/8.sup.c                                          0.50        3/4      0/8                                                      1.00        3/4      0/8                                                      2.00        2/4      0/8                                                      4.00        0/4      .sup. 0/8.sup.c                                          24.00       nd       0/8                                            125       0.25        1/4      0/8                                                      0.50        0/4      0/8                                                      1.00        1/4      0/8                                                      2.00        0/4      1/8                                                      4.00        0/4      1/8                                                      6.00        nd       1/8                                                      8.00        nd       0/8                                                      24.00       nd       0/8                                            130       0.25        4/4      0/8                                                      0.50        3/4      0/8                                                      1.00        2/4      0/8                                                      2.00        0/4      0/8                                                      4.00        0/4      0/4                                                      6.00        nd       0/8                                                      8.00        nd       0/8                                                      24.00       nd       0/8                                            131       0.25        4/4      .sup. 0/8.sup.c                                          0.50        3/4      0/8                                                      1.00        4/4      0/8                                                      2.00        2/4      0/8                                                      4.00        2/4      0/8                                                      6.00        nd       0/8                                                      8.00        nd       0/8                                                      24.00       nd       0/8                                            ______________________________________                                         .sup.a For definitions refer to Tables III, IV and V.                         .sup.b Wet dog shakes.                                                        .sup.c Exhibited hyperactivity.                                          

                  TABLE VII                                                       ______________________________________                                        Intraperitoneal Evaluation of Compounds 113 and 115 in Rats                           Time,     Dose,           Dose,                                       Compound                                                                              h         mg/kg   MES.sup.a                                                                             mg/kg Tox.sup.b                             ______________________________________                                        113     0.25      6.0     3/4     220   0/8                                           0.50              2/4           0/8                                           1.00              3/4           1/8                                           2.00              0/4           4/8                                           6.00              nd.sup.c      0/8                                           24.00             nd.sup.c      0/8                                           0.25      4.8     3/4     180   nd.sup.c                                      0.50              3/4           nd.sup.c                                      1.00              2/4           nd.sup.c                                      2.00              nd.sup.c      2/4                                           4.00              nd.sup.c      1/8                                   115     0.25      4.0     2/4     nd.sup.c                                            0.50              3/4                                                         1.00              3/4                                                         2.00              2/4                                                         0.50      2.0     1/4     nd.sup.c                                            1.00              1/4                                                 ______________________________________                                         .sup.a Number of animals protected from electroshock seizures/number of       animals tested.                                                               .sup.b Number of animals exhibiting neurotoxicity/number of animals           tested.                                                                       .sup.c nd = not determined.                                              

                  TABLE VIII                                                      ______________________________________                                        Special Intraperitoneal Rat Quantitation Data for                             Compounds 113 and 115.                                                        ______________________________________                                                   Time,   Dose,                                                      Compound   h       mg/kg     MES.sup.a                                                                           ED50.sup.c                                 ______________________________________                                        113        0.25    1.2       0/8   4.0                                                           3.6       5/8   (2.4-5.6)                                                     4.5       3/8                                                                 7.0       7/8                                              115        0.50    1.0       0/8   2.95                                                          2.0       3/8   (2.2-4.1)                                                     3.0       3/8                                                                 3.5       4/8                                                                 4.0       7/8                                              ______________________________________                                                Time,    Dose,                                                        Compound                                                                              h        mg/kg   Tox.sup.b                                                                           ED50.sup.c                                                                           .sup.d PI, MES                          ______________________________________                                        13      2.00     110     0/8   269.9  67.4                                                     180     2/8   (198.3-                                                         220     4/8   451.4)                                                          440     6/8                                                  15      0.25-     8      0/2   >64    >21.7                                           24        16     0/2                                                                    32     0/2                                                                    64     0/2                                                  ______________________________________                                         .sup.a Number of animals protected from electroshock seizures/number of       animals tested.                                                               .sup.b Number of animals exhibiting neurotoxicity/number of animals           tested.                                                                       .sup.c ED50 and TD50 values are in milligrams/kilogram of test drug           delivered intraperitoneally.                                                  .sup.d PI = protective index (TD50/MES ED50). Numbers in parenthese are       95% confidence interval.                                                 

For compounds which are water soluble (as are the majority of compoundsincluded in this application), the ADD program provides an initial oralevaluation in rats, identical to the phase I tests previously indicatedfor mice, except that mice are given the candidate drug byintraperitoneal injection. This oral screen is designated as phase VI.

As a result of the favorable protective indices, compounds 12 and 27were evaluated for oral activity in rats. Also included was thep-fluorobenzylamine derivative, 21 and dimedone 36. This data is shownin Table IX.

                                      TABLE IX                                    __________________________________________________________________________    Phase VI Oral Rat Data                                                              Dose,                                                                             Time,                                                               Compound                                                                            mg/kg                                                                             h   MES.sup.a                                                                         Tox.sup.b                                                                        ED50.sup.c                                                                          TD50.sup.c                                                                          PI.sup.c                                     __________________________________________________________________________     12   50  0.25                                                                              2/4 0/4                                                                              26.75 >500  18.69                                                  0.50                                                                              4/4 0/4                                                                              (16.30-                                                                             (nd)                                                         1.00                                                                              3/4 0/4                                                                              38.10)                                                             2.00                                                                              2/4 0/4                                                                   4.00                                                                              2/4 0/4                                                          21   50  0.25                                                                              2/4 0/4                                                                              49.26 >230  4.70                                                   0.50                                                                              2/4 0/4                                                                              (34.00-                                                                             (nd)                                                         1.00                                                                              1/4 0/4                                                                              77.69)                                                             2.00                                                                              2/4 0/4                                                                   4.00                                                                              3/4 0/4                                                          27   10  0.25                                                                              3/4 0/4                                                                              5.79  >380  65.63                                                  0.50                                                                              4/4 0/4                                                                              (3.98-                                                                              (nd)                                                         1.00                                                                              4/4 0/4                                                                              7.38)                                                              2.00                                                                              4/4 0/4                                                                   4.00                                                                              3/4 0/4                                                                6  0.25                                                                              nd  nd                                                                    0.50                                                                              3/4 0/4                                                                   1.00                                                                              2/4 0/4                                                                   2.00                                                                              1/4 0/4                                                          36   60  0.25                                                                              3/4 0/4                                                                              30.13 >250  8.30                                                   0.50                                                                              3/4 0/4                                                                              (14.91-                                                                             (nd)                                                         1.00                                                                              0/4 0/4                                                                              54.08)                                                             2.00                                                                              0/4 0/4                                                                   4.00                                                                              0/4 0/4                                                         107   50  0.25                                                                              2/4 0/4                                                         109   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              2/4 0/4                                                                   1.00                                                                              2/4 0/4                                                                   2.00                                                                              1/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         112   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         113   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         115   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         116   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         119   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              3/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         121   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              3/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                         122   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              4/4 0/4                                                         123   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         124   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              3/4 0/4                                                         125   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         126   50  0.25                                                                              2/4 0/4                                                                   0.50                                                                              3/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              3/4 0/4                                                                   4.00                                                                              2/4 0/4                                                         127   50  0.25                                                                              1/4 0/4                                                                   0.50                                                                              2/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              2/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         130   50  0.25                                                                              1/4 0/4                                                                   0.50                                                                              1/4 0/4                                                                   1.00                                                                              2/4 0/4                                                                   2.00                                                                              3/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         131   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              4/4 0/4            2.004/40/4                                   138   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              0/4 0/4                                                                   1.00                                                                              0/4 0/4                                                                   2.00                                                                              2/4 0/4                                                                   4.00                                                                              0/4 0/4                                                         142   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              0/4 0/4                                                                   1.00                                                                              0/4 0/4                                                                   2.00                                                                              0/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         144   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              0/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              1/4 0/4                                                                   4.00                                                                              4/4 0/4                                                         146   50  0.25                                                                              1/4 0/4                                                                   0.50                                                                              3/4 0/4                                                                   1.00                                                                              4/4 0/4                                                                   2.00                                                                              4/4 0/4                                                                   4.00                                                                              2/4 0/4                                                         147   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              2/4 0/4                                                                   2.00                                                                              1/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         148   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              2/4 0/4                                                                   1.00                                                                              2/4 0/4                                                                   2.00                                                                              2/4 0/4                                                                   4.00                                                                              3/4 0/4                                                         149   50  0.25                                                                              4/4 0/4                                                                   0.50                                                                              4/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              1/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         150   50  0.25                                                                              2/4 0/4                                                                   0.50                                                                              2/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              1/4 0/4                                                                   4.00                                                                              2/4 0/4                                                         151   50  0.25                                                                              3/4 0/4                                                                   0.50                                                                              1/4 0/4                                                                   1.00                                                                              1/4 0/4                                                                   2.00                                                                              2/4 0/4                                                                   4.00                                                                              0/4 0/4                                                         152   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              1/4 0/4                                                                   1.00                                                                              1/4 0/4                                                                   2.00                                                                              3/4 0/4                                                                   4.00                                                                              2/4 0/4                                                         153   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              2/4 0/4                                                                   1.00                                                                              3/4 0/4                                                                   2.00                                                                              3/4 0/4                                                                   4.00                                                                              1/4 0/4                                                         154   50  0.25                                                                              0/4 0/4                                                                   0.50                                                                              0/4 0/4                                                                   1.00                                                                              0/4 0/4                                                                   2.00                                                                              0/4 0/4                                                                   4.00                                                                              0/4 0/4                                                         phenytoin            29.80 >3000.sup.e                                                                         >100                                                              (21.9-                                                                        38.9)                                                    carbam-              8.50  813.sup.e                                                                           95.7                                         azepine              (3.39-                                                                              (489-                                                                   10.5) 1234)                                              valproate            490   280.sup.e                                                                           0.57                                                              (351- (191-                                                                   728)  353)                                               __________________________________________________________________________     .sup.a Maximal electroshock test (refer to Table III for definition).         .sup.b Toxicity (refer to Table IV).                                          .sup.c Refer to Table III for definition.                                     .sup.e Tox data based on ataxia.                                              nd = not determined.                                                     

As previously noted in mice, 12 and 27 displayed excellent protection(18.69 and 65.63 respectively). The toxicity evaluation for thecommercial agents as previously indicated was based on the onset ofataxia. None of the compounds in this report displayed ataxia. Compound12 was subjected to a special ip rate screening evaluation (Table X). Notoxicity was noted at 100 mg/kg throughout the four hour evaluation.

                  TABLE X                                                         ______________________________________                                        Special ip Rat Screening for Methyl                                           4-(benzyl)amino-6-methyl-2-oxocyclohex-                                       3-en-1-oate (12)                                                              Dose,                   Activity                                              mg/kg    Time, h        MES.sup.a                                                                             Tox.sup.b                                     ______________________________________                                        100      0.25           4/4     0/4                                                    0.50           4/4     0/4                                                    1.00           4/4     0/4                                                    2.00           4/4     0/4                                                    4.00           3/4     0/4                                           ______________________________________                                         .sup.a Maximal electroshock test (refer to Table III for definition).         .sup.b Toxicity (refer to Table III).                                    

                  TABLE X-A                                                       ______________________________________                                        Intraperitoneal (ip) toxicity of                                              Compounds 27 and 36 in rats (100 mg/kg).                                      Time,    Comp.   # Resp/     Comp. # Resp/                                    h        27      # Tested.sup.a                                                                            36    # Tested.sup.a                             ______________________________________                                        0.25             0/8               5/8                                        0.50             3//8              7/8                                        1.00             6/8               6/8                                        2.00             7/8               6/8                                        4.00             2/8               3/8                                        6.00             1/8               3/8                                        8.00             0/8               nd.sup.b                                   24.00    .sup. 2/8.sup.c                                                                       0/8                                                          ______________________________________                                         .sup.a Number of animals displaying neurotoxicity/number of animals           tested.                                                                       .sup.b nd = not determined.                                                   .sup.c 2 animals died.                                                   

Corneal kindling studies were performed in our laboratories on 12 and 27and the results are shown in Tables XI and XII and FIGS. 1A and 1B.Comparative data for the commercial products are included. Seizuresevoked in electroshock-kindled rats provide a suitable model consistentwith complex partial seizures evolving into generalized motor seizuresin humans.

                  TABLE XI                                                        ______________________________________                                        Corneal Kindling Rat Data.sup.a                                                                                  95%                                                          Time of          Confidence                                 Compound  Route   test, h  ED50    interval                                   ______________________________________                                        12        po      0.5      41.9    34.0-51.6                                  27        po      0.5      31.2    18.2-64.2                                  clonazepam.sup.b                                                                        po      1        0.70    0.53-1.02                                  carbamazepine.sup.b                                                                     po      1        28.90    7.73-75.59                                phenytoin.sup.b                                                                         po      0.5      >100                                               phenytoin.sup.b                                                                         ip      0.5      48.25   24.57-78.36                                valproate.sup.b                                                                         po      0.5      117.41   67.98-189.02                              ______________________________________                                         .sup.a Rats kindled to Stage 5. Endpoint was reduction from Stage 5 to        Stage 4.                                                                      .sup.b Data provided by the ADD Program.                                 

                  TABLE XII                                                       ______________________________________                                        Rat Kindling Data for Methyl 4-benzylamino-6- methyl-2-                       oxocyclohex-3-en-1-oate (12) and Methyl 4-(p-chloro)                          phenylamino-2-oxocyclohex-3-en-1-oate (27)                                                                Ave.                                                      Dose,               seizure                                           Compound                                                                              mg/kg    % Reduction                                                                              score.sup.a                                                                          S.E.M..sup.b                                                                         N.sup.c                             ______________________________________                                        12      50       17                        6                                          60       23                        6                                          75       75                       46                                  27       0        0         4.9    0.042  57                                          20       40         3.0    0.700  12                                          30       40         3.0    0.760  11                                          40       49         2.6    0.880   7                                          50       87         1.7    0.890   9                                  ______________________________________                                         .sup.a Ranking system: 0 = no effect; 1 = immobility; 2 = facial clonus,      head nodding; 3 = facial clonus and rearing; 4 = forelimb clonus and          rearing; 5 = forelimb clonus and falling.                                     .sup.b Standard error of the mean.                                            .sup.c Number of animals tested.                                         

Compound 27 provided an ED50 of 31.2 mg/kg. It should be noted thatphenytoin was inactive in this test via the oral route. The ED50 datafor 27 of 31.2 mg/kg compares favorably with carbamazepine (28.90mg/kg).

Compounds 12 and 27 were evaluated in our laboratory for suppression ofamygdala kindled seizures. This data is shown in Table XIII andindicated no significant activity.

                  TABLE XIII                                                      ______________________________________                                        Effect of compounds 27 and 12 on Amygdala Kindled Seizures.sup.a                     Baseline.sup.b,c                                                                      27.sup.c (350                                                                           Baseline.sup.b,c                                                                        12.sup.c (500                                     (0.5% MC)                                                                             mg/kg)    (0.5% MC) mg/kg)                                     ______________________________________                                        Afterdischarge                                                                Amygdala:                                                                              76.7     79.8       78.6    73.9                                     Duration(s)                                                                            (±18.7)                                                                             (±19.0) (±13.1)                                                                            (±15.5)                               Cortex:  2.1      2.7        1.3     2.8                                      Latency(s)                                                                             (±0.5)                                                                              (±0.6)  (±0.3)                                                                             (±1.3)                                Duration(s)                                                                            83.4     79.6       92.0    78.9                                              (±15.2)                                                                             (±17.8) (±16.2)                                                                            (±9.4                                 Behavioral Seizure:                                                           Latency(s)                                                                             2.1       2.1       2.0     2.1                                               (±0.2) (±0.1) (±0.2)                                                                             (±0.1)                                Duration(s)                                                                            90.0      82.3      100.0   79.5                                              (±11.7)                                                                              (±17.0)                                                                              (±18.0)                                                                            (±10.8)                               Forelimb Clonus:                                                              Latency(s)                                                                             5.6       9.2       8.7     9.3                                               (±3.0) (±6.8) (±4.3)                                                                             (±4.1)                                Duration(s)                                                                            54.8      45.3      41.7    44.2                                              (±8.2) (±7.2) (±17.2)                                                                            (±13.2)                               Seizure  5.0       5.0       5.0     5.0                                      Stage:   (±0.0) (±0.0) (±0.0)                                                                             (±0.0)                                ______________________________________                                         .sup.a See experimental section for details.                                  .sup.b MC = methyl cellulose.                                                 .sup.c Data in parenthesis represents the standard deviation based on N =     8 animals for 27 and N = 6 animals for 12.                               

Both 12 and 27 were evaluated in Phase V of the ADD Program evaluationscheme. Phase V provides quantification against bicuculline, picrotoxin,pentylenetetrazol, and strychnine. This screen provides information onthe mechanism of action of the anticonvulsant activity. Bicuculline,picrotoxin, and strychnine correspond to GABA inhibitory function,chloride channel inhibition and inhibition by glycine respectively.Compound 12 was uniformly inactive in all tests at doses of 12.5, 25, 50and 100 mg/kg. Compound 27 was also uniformly inactive in these tests.While not protecting the animals, 27, contrary to other commercialanticonvulsants (e.g., phenytoin), did not lower the threshold to thesechemostimulants. In addition, 27 was inactive in the benzodiazepinereceptor binding evaluation, the GABA receptor binding test and theadenosine uptake assay. In view of the recent reports that5-fluoro-4-oxopentanoic acid and 3,5-dioxocyclohexanecarboxylic acidinhibit GABA aminotransferase and were classified as "Class IV"inactivators, the starting β-hydroxyketones were tested and found to beinactive in phase I evaluations. This fact, together with the rapidonset of action of 12 and 27 would preclude their acting as prodrugs.From the results of the test data set out above, it appears that thepresence or absence of several structures may effect anticonvulsantactivity.

For anticonvulsant activity, primary amines must be employed aspyrrolidine and morpholine analogs, i.e., where instead of a primaryamine adjacent to R³, the nitrogen is part of a neterocyclic radical,were found to be uniformly inactive. It appears that the primary amineshould be attached directly, or through a methylene, ethylene or aminobridge, to an aromatic ring. The condensation of β-hydroxyketo ester 3(R═CO₂ CH₃ ; R¹ ═CH₃ ; R² ═H) with N-aminomorpholine produced the twoisomers, 33 and 34. However, neither was active in phase I evaluations.In addition, it was observed that in proceeding through the homologousseries from the active unsubstituted benzylamine analog 12 to theunsubstituted phenylamine compound 24, activity was lost. Similarly,other unsubstated phenylamines, 17 and 29, were inactive.

The anticonvulsant activity data further showed that while a methyl ordimethyl functionality at position 6 increases anticonvulsant activity,phenyl substitution 11 produces inactive compounds.

The anticonvulsant activity when there was a ester functionality atposition 1 was found to vary widely. Two dimedone analogs 19 and 36 havealso proved to be potent anticonvulsants. Phase II (Table V) and PhaseVI (Table VI) data for 36 indicates that the protective index in mice ismodest, while in rats anticonvulsant activity is lost after 1 hour.Thus, it appears that for maximum sustained activity and safety, thecarbomethoxy function should be present.

In view of the highly active 12, a systematic evaluation of theelectronic and steric effects involved in para substitution wasundertaken. The substituted benzylamines 16, 17, 18, 20 and 21 providedonly a slight modification in activity compared with 12, with only 21providing any significant activity in Phase II evaluation, establishingthat activity may reside in the +σ, +π quadrant. The fact that theenaminone of aniline, 24, the starting compound in our analysis wasinactive in anticonvulsant evaluations was unexpected. Nevertheless,with the exceptions of 32 (comparable to inactive 18 in the benzylamineseries) and 35, anticonvulsant activity was observed in the series,i.e., 26, 27, 28, 29, 30, 31, 32 and 35. Thus the conclusion thatanticonvulsant activity can be enhanced by para substitution to the +σ,+π quadrant as well as the -σ, +π quadrant appears valid.

Due to the similarity in anticonvulsant spectrum to phenytoin, it seemedlogical to depict each of the active enaminones, 12 and 27, against thatof phenytoin. This is shown in FIGS. 2A, 2B and 2C. Furthermore, thelack of enhanced anticonvulsant activity in the benzylamine series maybe due to the lack of a -I effect with the para substituents due to themethylene bridge which effectively blocks this electronic contribution.This is shown in FIGS. 3A and 3B. As noted by Topliss, para-fluorosubstitution produces a minimal change in σ and π effects compared tothe unsubstituted compound. This is borne out in the anticonvulsantactivity of 21. Steric effects in the benzylamine series cannot beoverlooked. FIGS. 2A, 2B and 2C indicates an increased distance from thephenyl ring to the carbonyl group of 12 compared to phenytoin and 27.

The aniline series bears out the conclusion that a -I effect enhancesactivity, and that strong +π groups enhance activity. Comparingpara-chlorobenzylamine 16 to para-chlorophenylamine 27,para-methylbenzylamine 17 to para-methylaniline 28,para-nitro-benzylamine 20 to para-nitroaniline 29, it is clear thatactivity is enhanced in all cases. In addition, the para hydroxy phenylanalog, 35, is inactive which parallels the metabolic inactivation ofphenytoin. Thus, the active anticonvulsant region of the enaminones cantentatively be outlined as indicated in FIGS. 2A, 2B, and 2C.

While the present invention has been described in connection with aspecific embodiment, it is understood that modifications and variationsmay be resorted to without departing from the spirit and scope of theinvention. As those of normal skill in the art will readily appreciatesuch modifications and variations, together with other equivalentembodiments, are within the purview and scope of the appended claims.

We claim:
 1. An enaminone having the formula: ##STR8## wherein R is fromthe group consisting of COOCH₃ and COOC₂ H₅ ;R¹ is from the groupconsisting of H and CH₃ ; R² is from the group consisting of H when R¹is CH₃ and CH₃ when R¹ is H; and R³ is from the group of first radicalsconsisting of benzyl, phenethyl, disubstituted phenyl and trisubstitutedphenyl, wherein the substituted species are second radicals havingpositive lipophilicity selected fromthe group consisting of F, Cl, Br,and I.
 2. The enaminone of claim 1 wherein R³ is from the groupconsisting of CH₂ C₆ H₅ and (CH₂)₂ C₆ H₅.
 3. The enaminone of claim 2wherein R³ is CH₂ C₆ H₅.
 4. An enaminone having the formula: ##STR9##wherein R is COOCH₃, R¹ is CH₃, R² is H, and R³ is CH₂ C₆ H₅.
 5. Apharmaceutical composition for alleviating convulsive seizurescomprising a therapeutically effective amount of an enaminone of claim 1in a pharmaceutically acceptible vehicle.
 6. A pharmaceuticalcomposition for alleviating convulsive seizures comprising atherapeutically effective amount of an enaminone of claim 2 in apharmaceutically acceptible vehicle.
 7. A pharmaceutical composition foralleviating convulsive seizures comprising a therapeutically effectiveamount of an enaminone of claim 4 in a pharmaceutically acceptiblevehicle.